Polyhalogen-substituted cinnamic acids and cinnamic acid derivatives and a process for the preparation of polyhalogen-substituted cinnamic acids and cinnamic acid derivatives

ABSTRACT

Polyhalogenated cinnamic acids and cinnamic acid derivatives are prepared by reacting diazonium salts accessible from polyhalogenated anilines with acrylic acid or acrylic acid derivatives in the presence of a homogeneous, palladium-containing catalyst at about −5 to about +100° C. Some of the cinnamic acids and cinnamic acid derivatives obtainable in this way are new. Cinnamic acids and cinnamic acid derivatives which can be prepared according to the invention can be used for the preparation of indanones which are precursors for agro- and pharmaceutical chemicals and for substances having liquid-crystalline properties.

BACKGROUND

The present invention relates to new polyhalogen-substituted cinnamicacids and cinnamic acid derivatives and a process for the preparation ofknown and new polyhalogen-substituted cinnamic acids and cinnamic acidderivatives.

Known halogen-substituted cinnamic acids and cinnamic acid derivativesare intermediates for the production of agrochemicals andpharmaceuticals (see DE-A 22 44 761, WO 95/30645, WO 94/26692, WO94/7893, WO 94/26693 and U.S. Pat. No. 5,753,655).

2,4-Difluorocinnamic acid and its esters of the formula (II) can beprepared by reacting benzyl halides of the formula (I) with aceticanhydride or benzaldehydes of the formula (I) with malonic acid ormalonic acid esters.

The following reaction equation illustrates this:

A disadvantage here is the high reaction temperature needed, theunsatisfactory yield and the difficult accessibility of the compounds ofthe formula (I). Monatshefte der Chemie 90, 680 (1959) describes thereaction of 2,4-difluorobenzaldehyde with acetic anhydride at 180° C.,2,4-difluorocinnamic acid being obtained in a 77% yield.

In another route for the preparation of a halogen-substituted cinnamicacid derivative, 2,4-difluoro-bromobenzene is used as a startingmaterial and this is reacted with acrylic acid with addition oftriphenylphosphinepalladium dichloride and potassium carbonate indimethylformamide at 145 to 150° C. in the course of 6 hours. Thecorresponding cinnamic acid derivative is obtained in a yield of only54% (Russ. J. Org. Chem. 33 (4), 563-569 (1997)). The yield is stillunsatisfactory here and high reaction temperatures and long reactiontimes are also needed.

Finally, it is known from EP-A-584 043 that compounds of the typeAr—CHR_(a)—CHR_(b)R_(c) can be prepared if diazonium salts of the typeAR—N₂⊕ are reacted with compounds of the type CR_(a)═CR_(b)R_(c) withformation of compounds of the type Ar—CHR_(a)═CR_(b)R_(c) and thereaction is carried out in the presence of homogeneous palladiumcatalysts and with addition of 1 to 10 equivalents of base. This processis particularly suitable for the preparation of compounds in which theAr radical is substituted by a sulfonic acid group, i.e. a stronglypolar group. In addition to this restriction, it is disadvantageous thatin this process large amounts of bases have to be added, which meansadditional costs and makes necessary a complicated work-up of thereaction mixture.

EP-A-584 264 describes a similar process to that of EP-A-584 043.However, the reaction is carried out in the additional presence ofarylphosphanes, which is associated with further costs and furtheradditional outlay.

There is thus still the need for a process for the preparation ofpolyhalogenated cinnamic acids and cinnamic acid derivatives in which,in a simple manner, at moderate temperatures, with short reaction times,without addition of base and without necessary addition ofarylphosphanes, the desired products are accessible in a higher yieldthan hitherto.

SUMMARY

The invention relates to a process for preparing a polyhalogenatedcinnamic acid or a cinnamic acid derivative having the formula (III)

wherein R¹, R², R³ and R⁴ are identical or different and in each caserepresent hydrogen, fluorine, chlorine or bromine, at least two of theseradicals being other than hydrogen and X represents OR⁵ or N(R⁶)(R⁷)where R⁵ represents hydrogen or optionally substituted C₁-C₁₀-alkyl,optionally substituted phenyl or benzyl and R⁶ and R⁷ are identical ordifferent and in each case represent optionally substituted C₁-C₁₀-alkyland R⁸ represents hydrogen, chlorine, bromine or optionally substitutedC₁-C₁₀-alkyl. The process comprises reacting (1) a diazonium salt of theformula (IV)

wherein R¹, R², R³ and R⁴ have the meaning indicated in formula (III)and A⊖ represents an equivalent of halide, hydrogensulfate, nitrate,acetate or tetrafluoroborate ions or ½ an equivalent of sulfate ions or⅓ an equivalent of phosphate ions,with (2) an acrylic acid or an acrylicacid derivative of the formula (V)

wherein X has the meaning indicated in formula (III) and R⁸ representshydrogen, chlorine, bromine or optionally substituted C₁-C₁₀-alkyl, inthe presence of a homogeneous, palladium-containing catalyst at atemperature ranging from about −5 to about +100° C.

The invention also relates to a polyhalogenated cinnamic acid or acinnamic acid derivative having the formula (III′):

wherein R^(2′) represents chlorine and R^(4′) represents fluorine, orR^(2′) represents fluorine and R^(4′) represents chlorine.

The invention also relates to a method for preparing an indanonederivative of the formula (VIIa):

wherein R¹, R², R³ and R⁴ are identical or different and in each caserepresent hydrogen, fluorine, chlorine or bromine, at least two of theseradicals being other than hydrogen and R⁸ represents hydrogen, chlorine,bromine or optionally

wherein R¹, R², R³, R⁴ are identical or different and in each caserepresent hydrogen, fluorine, chlorine or bromine, at least two of theseradicals being other than hydrogen and X represents OR⁵ or N(R⁶)(R⁷),where R⁵ represents hydrogen or optionally substituted C₁-C₁₀-alkyl,optionally substituted phenyl or benzyl and R⁶ and R⁷ are identical ordifferent and in each case represent optionally substituted C₁-C₁₀-alkyland R⁸ represents hydrogen, chlorine, bromine or optionally substitutedC₁-C₁₀-alkyl, and (b) cyclizing the hydrogenated cinnamic acid orcinnamic acid derivative formed in step (a), thereby forming theindanone derivative of the formula (VIIa).

The invention also relates to a method for method for preparing anindanone derivative of the formula (VIIb)

wherein R¹, R², R³ and R⁴ are identical or different and in each caserepresent hydrogen, fluorine, chlorine or bromine, at least two of theseradicals being other than hydrogen and R⁹ represents COOH, CONH₂ orCOOR¹⁰, wherein R¹ denotes C₁-C₄-alkyl. The method comprises (a)hydrogenating a polyhalogenated cinnamic acid or cinnamic acidderivative having the formula (III)

wherein R¹, R², R³ and R⁴ are identical or different and in each caserepresent hydrogen, fluorine, chlorine or bromine, at least two of theseradicals being other than hydrogen and X represents OR⁵ or N(R⁶)(R⁷),where R⁵ represents hydrogen or optionally substituted C₁-C₁₀-alkyl,optionally substituted phenyl or benzyl and R⁶ and R⁷ are identical ordifferent and in each case represent optionally substituted C₁-C₁₀-alkyland R⁸ represents hydrogen, chlorine or bromine, and (b) cyclizing thehydrogenated cinnamic acid or cinnamic acid derivative formed in step(a), thereby forming the indanone derivative of the formula (VIIa)

wherein R¹, R², R³, R⁴ and R⁸ have the meaning indicated in formula(III) above and (c) converting the indanone derivative of the formula(VIIa), in case of R⁸ representing hydrogen after halogenation, by apalladium-catalysed carbonylation reaction with carbon monoxide and asuitable nucleophile, and thereby forming the indanone derivative of theformula (VIIb).

These and other features, aspects, and advantages of the presentinvention will become better understood with reference to the followingdescription and appended claims.

DESCRIPTION

A process for the preparation of polyhalogenated cinnamic acids andcinnamic acid derivatives of the formula (III) has now been found

in which

R¹, R², R³ and R⁴ are identical or different and in each case representhydrogen, fluorine, chlorine or bromine, at least two of these radicalsbeing other than hydrogen and

X represents OR⁵ or N(R⁶)(R⁷), where

R⁵ represents hydrogen, optionally substituted C₁-C₁₀-alkyl, optionallysubstituted phenyl or benzyl and

R⁶ and R⁷ are identical or different and in each case representoptionally substituted C₁-C₁₀-alkyl and

R⁸ represents hydrogen, chlorine, bromine or optionally substitutedC₁-C₁₀-alkyl,

which is characterized in that a diazonium salt of the formula (IV)

in which

R¹, R², R³ and R⁴ have the meaning indicated in formula (III) and

20A⊖ represents an equivalent of halide, hydrogensulfate, nitrate,acetate or tetrafluoroborate ions or ½ an equivalent of sulfate ions or⅓ an equivalent of phosphate ions,

is reacted with acrylic acid or an acrylic acid derivative of theformula (V)

in which

X has the meaning indicated in formula (III) and

R⁸ represents hydrogen, chlorine, bromine or optionally substitutedC₁-C₁₀-alkyl, in the presence of a homogeneous, palladium-containingcatalyst at a temperature ranging from about −5 to about +100° C.

The process according to the invention is most preferably carried outwithout addition of base. Generally, the process is carried out with 0.5moles or below, preferably 0.1 moles or below and more preferably 0.05moles base per mole of diazonium salt of the formula (IV).

Advantageously and most preferably the process according to theinvention is carried without the addition of arylphosphanes. Generally,the process is carried out with 4 moles or below, preferably 1 moles orbelow and more preferably 0.1 moles of arylphosphanes per mole ofpalladium.

If the radicals R⁵, R⁶, R⁷ and R⁸ are optionally substituted alkylradicals, suitable substituents can be, for example, halogen, hydroxylor C₆-C₁₂-aryl radicals. 1 or 2 of these substituents can be present,for example, per radical selected from the group consisting of R⁵, R⁶,R⁷ and R⁸.

Preferably, R¹ represents hydrogen or chlorine, R² represents hydrogen,fluorine, chlorine or bromine, R³ represents hydrogen or chlorine and R⁴represents fluorine or chlorine, at least one of the radicals R¹, R² andR³ being other than hydrogen.

R⁵ preferably represents hydrogen, methyl, ethyl, isopropyl or benzyl.R⁶ and R⁷ preferably represent methyl or ethyl. R⁸ preferably representshydrogen or methyl. A^(θ) preferably represents an equivalent ofchloride, hydrogensulfate or acetate or 1/2 an equivalent of sulfate.

Suitable homogeneous, palladium-containing catalysts are, for example,palladium(II) and palladium(0) compounds such as PdCl₂, PdBr₂, Pd(NO₃)₂,H₂PdCl₄, Pd(CH₃COO)₂, Na₂PdCl₄, K₂PdCl₄, Pd(II) acetyl-acetonate,tetra-(triphenylphosphine)Pd and tris-(dibenzylidene-acetone)Pd₂. PdCl₂,Pd(CH₃COO)₂ and Pd(II) acetylacetonate are preferred.

The respective palladium-containing catalyst can be employed, forexample, in an amount ranging from about 0.001 to about 10 mol %,preferably based on the diazonium salt of the formula (IV).

Preferred reaction temperatures are those ranging from about +20 toabout +80° C., in particular those ranging from about +40 to about +65°C.

The process according to the invention can optionally be carried outwith the addition of simple solvents. Suitable simple solvents are, forexample, water, alcohols, like for example C₁-C₆-alkyl alcohols,carboxylic acids, like for example formic acid, ethers, like for exampletetrahydrofuran and nitrites, like for example acetonitrile.

The diazonium salts of the formula (IV) can be prepared in a mannerknown per se (see, for example, Houben-Weyl, Volume X/3, pages 7 to 113)from the corresponding anilines by reaction with sodium nitrite inacidic aqueous solution or by reaction of methyl nitrite in acidicmethanol. The diazonium salts can be employed in the process accordingto the invention in the form of the reaction mixture obtained duringtheir preparation, preferably after the destruction of nitrite which maystill be present. Isolation of the diazonium salts is not necessary.

Preferred compounds of the formula (V) are acrylic acid, methacrylicacid, acrylamide and methacrylamide.

Based on 1 mol of diazonium salt of the formula (IV), it is possible toemploy, for example, from about 0.5 to about 2 mol of acrylic acid oracrylic acid derivatives of the formula (V). This amount is preferablyfrom about 0.9 to about 1.5 mol.

The process according to the invention can be carried out so that, forexample, firstly an aniline of the formula

in which

R¹, R², R³ and R⁴ have the meaning indicated in formula (III), isconverted with sodium nitrite in aqueous sulfuric acid solution or withan alkyl nitrite such as methyl, ethyl, butyl or amyl nitrite,preferably methyl nitrite, in acidic, e.g. sulfuric acid-containingmethanol, into a diazonium salt of the formula (IV), nitrite which maybe present in the reaction mixture obtained is destroyed by addition ofamidosulfonic acid, the reaction mixture treated in this way is addeddropwise at reaction temperature to a mixture of acrylic acid or anacrylic acid derivative of the formula (V) with a homogeneous,palladium-containing catalyst and optionally a simple solvent such aswater, methanol, ethanol or isopropanol and optionally after a stirringtime the prepared product of the formula (III), if appropriate aftercooling and/or dilution with water, is separated off, e.g. byfiltration, distillation or phase separation.

The process according to the invention has the advantages that itproduces polyhalogen-substituted cinnamic acids and cinnamic acidderivatives in high yields in a simple manner, at low temperatures, inshort reaction times, with low amounts or preferably without additionsof bases and with low amounts or preferably without additions ofarylphosphanes. Moreover, no special solvents such as amidic solventsand especially dimethylformamide are needed.

The present invention further relates to new polyhalogenated cinnamicacids and cinnamic acid derivatives of the formula (III′)

in which

R^(2′) represents chlorine and R^(4′) represents fluorine or

R^(2′) represents fluorine and R^(4′) represents chlorine.

One possibility of preparation of the new compounds of the formula(III′) has been described above. Their utility is illustrated below.

The polyhalogenated cinnamic acids and cinnamic acid derivatives of theformula (III) including those of the formula (III′) can be converted byhydrogenation of the double bond (1st step) and subsequent cyclization(2nd step) into indanone derivatives of the formula

in which

R¹ to R⁴ have the meaning indicated in formula (III) and

R⁸ represents hydrogen, bromine, chlorine or optionally substitutedC₁-C₁₀-alkyl.

Compounds of the general formula (VIIa) in which R⁸ represents hydrogencan be converted in a manner known per se by halogenation into thecorresponding compounds of the general formula (VIIa) in which R⁸represents bromine or chlorine.

Furthermore, compounds of the general formula (VIIa) in which R⁸represents bromine or chlorine can be converted in a manner known perse, for example by palladium-catalysed carbonylation reactions withcarbon monoxide and a suitable nucleophile, into indanone derivatives ofthe formula (VIIb)

in whichR¹ to R⁴ have the meaning indicated in formula (III) and

R⁹ represents COOH, CONH₂ or COOR¹⁰, where

R¹⁰ denotes C₁-C₄-alkyl.

The 1st step can be carried out, for example, by hydrogenating withhydrogen in the presence of platinum or palladium, if appropriate atelevated pressure, and the 2nd step can be carried out, for example, byconverting the arylproprionic acids obtained into the corresponding acidchlorides and cyclizing these with the aid of Friedel-Crafts catalyststo give the indanones of the general formula (VIIa).

From these indanones and those of the formula (VIIb), agrochemical andpharmaceutical active compounds and liquid-crystalline materials areaccessible analogously to known processes (see, for example, WO95/29171, EP-A 538 134, EP-A 401 166 and JP-A 06-263 663).

The new compounds of the formula (III′) widen the range of the indanonesavailable and thus to prepare and to test potential active compounds inthe agrochemical and pharmaceutical field and also in the field ofliquid-crystalline substances.

The invention is further described in the following illustrativeexamples in which all parts and percentages are by weight unlessotherwise indicated.

EXAMPLES Example 1 2,4-Difluorocinnamic acid

62 ml of concentrated sulfuric acid were added to 236 ml of water, themixture was cooled to 5° C. and 38.7 g of 2,4-difluoroaniline wereadded. A solution of 23.9 g of sodium nitrite in 45 ml of water wasadded dropwise at 0 to 2° C. in the course of 40 minutes and the mixturewas stirred for 30 minutes. Sufficient amidosulfonic acid was then addedto destroy excess nitrite. 0.34 g oftris(dibenzylideneacetone)-dipalladium(0) was added to 25.8 g of acrylicacid and the diazonium salt solution was added dropwise at 40° C. overthe course of 4 hours and the mixture was stirred for 2 hours. After ithad been cooled to room temperature, 47.5 g of difluorocinnamic acidwere isolated by filtration (86% of theory; melting point: 203° C.).

Example 2 2,4-Difluorocinnamic acid

77.5 g of difluoroaniline were added dropwise at 0° C. to a mixture of124 ml of concentrated sulfuric acid and 472 ml of water. A solution of48.3 g of sodium nitrite in 90 ml of water was then added dropwise at 0°C. in the course of 30 minutes such that the temperature was maintained.The mixture was then stirred at 0° C. for 30 minutes. Excess nitrite wasdestroyed by the addition of amidosulfonic acid.

0.1 g of palladium(II) acetylacetonate was added to 54.8 g of acrylicacid and the mixture was warmed to 50° C. The diazonium salt solutionwas added dropwise at this temperature in the course of 4 hours and themixture was stirred for a further 2 hours. After it had been cooled toroom temperature, the solid was isolated by filtration, washed withwater and dried (99.6 g; 90% of theory; melting point: 203 to 205° C.).

Example 3 4-Bromo-2-fluorocinnamic acid

62 ml of sulfuric acid were added to 236 ml of water and the mixture wascooled to 5° C. 57.0 g of 4-bromo-2-fluoroaniline were added at thistemperature and a solution of 24.2 g of sodium nitrite in 45 ml of waterwas added dropwise at 0 to 2° C. in the course of 30 minutes and themixture was stirred for 20 minutes. 2.8 g of amidosulfonic acid werethen added. 5 ml of the diazonium salt solution were added dropwise at40° C. to 27.5 g of acrylic acid, 0.23 g of palladium(II)acetylacetonate was added and the residual diazonium salt solution wasadded dropwise in the course of 20 minutes. The mixture was stirred at40° C. for 4 hours. It was allowed to cool to room temperature and theproduct was isolated by filtration. After drying, 54.4 g of4-bromo-2-fluorocinnamic acid were present (74% of theory; meltingpoint: 218° C.).

Example 4 2,4-Dichlorocinnamic acid

Gaseous methyl nitrite was prepared from 35 g of sodium nitrite in amethanol (20 ml)/water (60 ml) mixture by addition of 30 ml of 50%strength sulfuric acid (30 ml), and was introduced at 0° C. into amixture of 250 ml of water, 60 ml of conc. sulfuric acid and 53.5 g of2,4-dichloroaniline. The mixture was stirred for 1 hour. Excess methylnitrite was removed by passing through a stream of nitrogen and additionof 3 g of amidosulfonic acid. This solution was added over the course of2 hours at 40° C. to a solution of 0.25 g of palladium(II)acetylacetonate and 30 g of acrylic acid and the mixture was stirred for2 hours. After cooling to room temperature, the precipitate was filteredand dried. 58.1 g of 2,4-dichlorocinnamic acid resulted (81% of theory;melting point: 230° C.).

Example 5 2,4-Difluorocinnamic acid

77.5 g of difluoroaniline were added dropwise at 0° C. to a mixture of124 ml of conc. sulfuric acid and 472 ml of water. A solution of 48.3 gof sodium nitrite in 90 ml of water was then added dropwise at 0° C.such that the temperature was maintained. The mixture was then stirredat 0° C. for 30 minutes. Excess nitrite was destroyed by the addition ofamidosulfonic acid.

0.34 g of palladium(II) acetate was added to 54.8 g of acrylic acid andthe mixture was warmed to 47° C. The diazonium salt solution was addeddropwise at this temperature in the course of 2 hours such that thetemperature did not exceed 49° C., then the mixture was stirred for afurther 2 hours. After it had been cooled to room temperature, the solidwas isolated by filtration, washed with water and dried. This afforded105.1 g of 2,4-difluorocinnamic acid (95% of theory; melting point204-205° C.).

Example 6 3-(2,4-Difluorophenyl)-2-methylacrylic acid

77.5 g of difluoroaniline were added dropwise at 0° C. to a mixture of124 ml of conc. sulfuric acid and 472 ml of water. A solution of 48.3 gof sodium nitrite in 90 ml of water was then added dropwise at 0° C.such that the temperature was maintained, then the mixture was stirredat 0° C. for 30 minutes. Excess nitrite was destroyed by the addition ofamidosulfonic acid.

0.34 g of palladium(II) acetate was added to 60.1 g of methacrylic acidand the mixture was warmed to 45° C. The diazonium salt solution wasadded dropwise at this temperature in the course of 2 hours such thatthe temperature did not exceed 50° C., then the mixture was stirred fora further 2 hours. After it had been cooled to room temperature, thesolid was isolated by filtration, washed with water and dried. 118.0 gof 3-(2,4-difluorophenyl)-2-methylacrylic acid resulted (85% of theory;melting point 140-142° C.).

Example 7 3-(2,4-Difluorophenyl)-propionic acid (not according to theinvention)

105 g of 2,4-difluorocinnamic acid from Example 5 were dissolved in 450ml of tetrahydrofuran and reacted with 5 g of palladium on active carbonwith stirring at 100° C. and a hydrogen pressure of 50 bar. After aconstant pressure had been achieved, the mixture was cooled to roomtemperature, the pressure was released, the palladium catalyst wasfiltered off and the solvent was removed by distillation. After dryingin vacuo, 104.1 g of 3-(2,4-difluorophenyl)-propionic acid (98% oftheory; melting point: 100-102° C.) were obtained.

Example 8 2,5-Difluoro-4-chlorocinnamic acid

98.2 g of 2,5-difluoro-4-chloroaniline were added dropwise at 0° C. to amixture of 124 ml of conc. sulfuric acid and 472 ml of water. A solutionof 48.3 g of sodium nitrite in 90 ml of water was then added dropwise at0° C. such that the temperature was maintained. The mixture was thenstirred at 0° C. for 30 minutes. Excess nitrite was destroyed by theaddition of amido-sulfonic acid.

0.34 g of palladium(II) acetate was added to 54.8 g of acrylic acid andthe mixture was warmed to 47° C. The diazonium salt solution was addeddropwise at this temperature in the course of 2 hours such that thetemperature did not exceed 49° C., then the mixture was stirred for afurther 2 hours. After it had been cooled to room temperature, the solidwas isolated by filtration, washed with water and dried. This afforded116.7 g of 2,5-difluoro-4-chlorocinnamic acid (89% of theory).

Example 9 2,5-Difluoro-3-chlorocinnamic acid

98.2 g of 2,5-difluoro-3-chloroaniline were added dropwise at 0° C. to amixture of 124 ml of conc. sulfuric acid and 472 ml of water. A solutionof 48.3 g of sodium nitrite in 90 ml of water was then added dropwise at0° C. such that the temperature was maintained. The mixture was thenstirred at 0° C. for 30 minutes. Excess nitrite was destroyed by theaddition of amidosulfonic acid.

0.34 g of palladium(II) acetate was added to 54.8 g of acrylic acid andthe mixture was warmed to 47° C. The diazonium salt solution was addeddropwise at this temperature in the course of 2 hours such that thetemperature did not exceed 49° C., then the mixture was stirred for afurther 2 hours. After it had been cooled to room temperature, the solidwas isolated by filtration, washed with water and dried. This afforded108.9 g of 2,5-difluoro-3-chlorocinnamic acid (83% of theory).

Example 10 2,3,4,5-Tetrachlorocinnamic acid

98.2 g of 2,3,4,5-tetrachloroaniline were added dropwise at 0° C. to amixture of 124 ml of conc. sulfuric acid and 472 ml of water. A solutionof 48.3 g of sodium nitrite in 90 ml of water was then added dropwise at0° C. such that the temperature was maintained. The mixture was thenstirred at 0° C. for 30 minutes. Excess nitrite was destroyed by theaddition of amidosulfonic acid.

0.34 g of palladium(II) acetate was added to 54.8 g of acrylic acid andthe mixture was warmed to 47° C. The diazonium salt solution was addeddropwise at this temperature in the course of 2 hours such that thetemperature did not exceed 49° C., then the mixture was stirred for afurther 2 hours. After it had been cooled to room temperature, the solidwas isolated by filtration, washed with water and dried. This afforded144.1 g of 2,3,4,5-tetrachlorocinnamic acid (84% of theory).

Example 11 3-(2,4-Difluorophenyl)propionic acid (not according to theinvention)

The procedure was as in Example 5, but the 2,4-difluorocinnamic acidobtained was not isolated. The aqueous-acidic product suspensionobtained was treated with 2 g of Pd/C (5% strength) at 50° C. withfurther stirring and heated to 100° C. It was then pressurized to 5 barof hydrogen. After constant pressure had been achieved, it was cooled toroom temperature, the pressure was released and the solid was filteredoff. The filter cake was taken up in methylene chloride, the palladiumcatalyst was filtered off and the solvent was removed. After drying invacuo, 100.5 g of 3-(2,4-difluorophenyl)propionic acid (90% of theory;melting point: 100° C.) were obtained.

Example 12 3-(2,4-Difluorophenyl)propionic acid (not according to theinvention)

The procedure was as in Example 11, but the addition of palladium onactive carbon was dispensed with. 98.3 g of 3-(2,4-difluorophenyl)propionic acid (88% of theory) were obtained.

Example 13 3-(2,4-Difluorophenyl)propionic acid (not according to theinvention)

The procedure was as in Example 5, but the 2,4-difluorocinnamic acidobtained was not isolated. The aqueous-acidic product suspensionobtained was rendered alkaline using sodium hydroxide solution andtreated with 2 g of Pd/C (5% strength) at 50° C. with further stirringand heated to 100° C. It was then pressurized to 5 bar of hydrogen.After constant pressure had been achieved, it was cooled to roomtemperature, the pressure was released and the palladium catalyst wasfiltered off. The alkaline product solution was acidified with sulfuricacid and the product precipitate was isolated by filtration. Afterdrying in vacuo, 95.0 g of 3-(2,4-difluorophenyl)propionic acid (85% oftheory) were obtained.

Example 14 4,6-Difluoroindan-1-one (Not According to the Invention)

Thionyl chloride (54.6 g) was added dropwise at 40° C. to a solution of3-(2,4-di-fluorophenyl)propionic acid (57 g) in methylene chloride (200ml). After reaction was complete, excess thionyl chloride and thesolvent were removed by distillation. The oily residue was addeddropwise at 40° C. to a suspension of aluminium chloride (88.5 g) inmethylene chloride (200 ml). The reaction mixture was added to dilutehydrochloric acid after 18 hours at 40° C. The aqueous phase wasseparated off and extracted once with methylene chloride (250 ml). Thecombined organic phases were freed from the solvent and then distilledin vacuo. 41 g of a colorless solid were obtained (m.p.: 103° C.).

Example 15 4,6-Dichloroindan-1-one (not according to the invention)

Thionyl chloride (36.9 g) was added dropwise at 40° C. to a solution of3-(2,4-di-chlorophenyl)propionic acid (43.8 g) in methylene chloride(200 ml). After reaction was complete, excess thionyl chloride and thesolvent were removed by distillation. The oily residue was addeddropwise at 40° C. to a suspension of aluminium chloride (53.3 g) inmethylene chloride (200 ml). The reaction mixture was added to dilutehydrochloric acid after 18 hours at 40° C. The aqueous phase wasseparated off and extracted once with methylene chloride (250 ml). Thecombined organic phases were freed from the solvent. The residue wasrecrystallized from cyclohexane. 30 g of a colorless solid (m.p.:115-116° C.) were obtained.

Example 16 5,7-Dichloroindan-1-one (not according to the invention)

Thionyl chloride (45.2 g) was added dropwise at 40° C. to a solution of3-(3,5-di-chlorophenyl)propionic acid (54.8 g) in methylene chloride(200 ml). After reaction was complete, excess thionyl chloride and thesolvent were removed by distillation. The oily residue was addeddropwise at 40° C. to a suspension of aluminium chloride (66.7 g) inmethylene chloride (200 ml). The reaction mixture was added to dilutehydrochloric acid after 18 hours at 40° C. The aqueous phase wasseparated off and extracted once with methylene chloride (250 ml). Thecombined organic phases were freed from the solvent. The residue wasrecrystallized from cyclohexane. 36 g of a colorless solid (m.p.:119-120° C.) were obtained.

Example 17

Analogously to Example 5, starting from 2-chloro-5-fluoroaniline,2-chloro-5-fluorocinnamic acid was prepared in a yield of 80% of theory.The melting point of this cinnamic acid was 182° C. and the ¹H-NMRspectrum showed characteristic absorptions at 6.6 ppm (d), 7.25 ppm (m),7.5 ppm (m) and 7.75 (m), recorded in DMSO.

Example 18

Analogously to Example 5, starting from 2-fluoro-5-chloro-aniline,2-fluoro-5-chloro-cinnamic acid was prepared in a yield of 81% oftheory. The melting point of this cinnamic acid was 183° C. and the¹H-NMR spectrum showed characteristic absorptions at 6.6 ppm (d), 7.25ppm (t), 7.45 ppm (m), 7.55 ppm (d) and 7.9 ppm (m), recorded in DMSO.

Although the present invention has been described in detail withreference to certain preferred versions thereof, other variations arepossible. Therefore, the spirit and scope of the appended claims shouldnot be limited to the description of the versions contained therein.

1. A process for preparing a compound of formula (III)

wherein R¹, R², R³ and R⁴ are identical or different and in each caserepresent hydrogen, fluorine, chlorine or bromine, at least two of theseradicals being other than hydrogen and X represents OR⁵ or N(R⁶)(R⁷),where R⁵ represents hydrogen or optionally substituted C₁-C₁₀-alkyl,optionally substituted phenyl or benzyl and R⁶ and R⁷ are identical ordifferent and in each case represent optionally substituted C₁-C₁₀-alkyland R⁸ represents hydrogen, chlorine, bromine, or optionally substitutedC₁-C₁₀-alkyl, the process comprising: reacting (1) an aniline of theformula (VI)

wherein R¹, R², R³ and R⁴ have the meaning indicated in formula (III)with sodium nitrite in aqueous sulfuric acid or sulfuric acid incombination with methanol, or with an alkyl nitrite selected from thegroup consisting of methyl, ethyl, butyl and amyl nitrite into adiazonium salt and reacting (2) the resulting reaction mixture with acompound of formula (V)

wherein X has the meaning indicated in formula (III) and R⁸ representshydrogen, chlorine, bromine or optionally substituted C₁-C₁₀-alkyl, inthe presence of a homogeneous, palladium-containing catalyst at atemperature ranging from about −5 to about +100° C.
 2. The processaccording to claim 1, wherein R¹ represents hydrogen or chlorine, R²represents hydrogen, fluorine, chlorine or bromine, R³ representshydrogen or chlorine and R⁴ represents fluorine or chlorine, at leastone of the radicals R¹, R² and R³ being other than hydrogen, R⁵represents hydrogen, methyl, ethyl, isopropyl or benzyl, R⁶ and R⁷represent methyl or ethyl, and R⁸ represents hydrogen or methyl.
 3. Theprocess according to claim 1, wherein, the palladium-containing catalystis selected from the group consisting of PdCl₂, PdBr₂, Pd(NO₃)₂,H₂PdCl₄, Pd(CH₃COO)₂, Na₂PdCl₄, K₂PdCl₄, Pd(II) acetylacetonate,tetra-(trisphenylphosphine)Pd, tris-(dibenzylidene-acetone)Pd₂ andwherein the palladium-containing catalyst is used in an amount rangingfrom about 0.001 to about 10 mol %, based on the diazonium salt of theformula (IV).
 4. The process according to claim 1, wherein from about0.5 to about 2 moles of compounds of formula (V) are employed, per moleof diazonium salt of the formula (IV).
 5. The process according to claim1, wherein the process is carried out without a base.
 6. The processaccording to claim 1, wherein, R¹, R², R³, R⁴, R⁸ has the meaningindicated in formula (III) and X represents OR⁵, where R⁵ representshydrogen.